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REVIEW published: 03 April 2017 doi: 10.3389/fcell.2017.00029

Organ-to-Organ Communication: A Drosophila Gastrointestinal Tract Perspective

Qiang Liu and Li Hua Jin*

Department of Genetics, College of Life Sciences, Northeast Forestry University, Harbin, China

The long-term maintenance of an organism’s homeostasis and health relies on the accurate regulation of organ-organ communication. Recently, there has been growing interest in using the Drosophila gastrointestinal tract to elucidate the regulatory programs that underlie the complex interactions between organs. Data obtained in this field have dramatically improved our understanding of how organ-organ communication contributes to the regulation of various aspects of the intestine, including its metabolic and physiological status. However, although research uncovering regulatory programs associated with interorgan communication has provided key insights, the underlying mechanisms have not been extensively explored. In this review, we highlight recent Edited by: findings describing gut-neighbor and neighbor-neighbor communication models in adults Simon Rousseau, McGill University, Canada and larvae, respectively, with a special focus on how a range of critical strategies Reviewed by: concerning continuous interorgan communication and adjustment can be used to Yiorgos Apidianakis, manipulate different aspects of biological processes. Given the high degree of similarity University of Cyprus, Cyprus Piero Crespo, between the Drosophila and mammalian intestinal epithelia, it can be anticipated that Consejo Superior de Investigaciones further analyses of the Drosophila gastrointestinal tract will facilitate the discovery of Científicas - IBBTEC, Spain similar mechanisms underlying organ-organ communication in other mammalian organs, *Correspondence: such as the human intestine. Li Hua Jin [email protected]; Keywords: Drosophila, gastrointestinal tract, interorgan communication, signaling network, organismal [email protected] homeostasis, innate immune system

Specialty section: This article was submitted to INTRODUCTION Signaling, a section of the journal The physiological systems of various multicellular organisms that communicate with each other are Frontiers in Cell and Developmental of significance for the regulation of homeostasis under varying environmental conditions (Nässel Biology et al., 2013; Droujinine and Perrimon, 2016). The close spatial association between organs within Received: 19 December 2016 an open circulation correlates with multiple aspects of development, fecundity, growth, metabolic Accepted: 15 March 2017 homeostasis, stress responses, and lifespan, the disruption of which underlies the loss of the optimal Published: 03 April 2017 or steady state (Amcheslavsky and Ip, 2012; Droujinine and Perrimon, 2013). How an organism Citation: instructs this process of communication is a question of great complexity. Liu Q and Jin LH (2017) An excellent model to explore organ-to-organ communication is the Drosophila gastrointestinal Organ-to-Organ Communication: A Drosophila Gastrointestinal Tract tract (GI tract). The gastrointestinal mono-layered tube, as a physical barrier, possesses a range of Perspective. critical defense strategies to ensure organismal health (Royet, 2011). The source of the signals with Front. Cell Dev. Biol. 5:29. respect to intestinal homeostasis is not confined to the GI tract. For example, the integral parts of doi: 10.3389/fcell.2017.00029 the GI tract, such as the intestinal trachea and enteric neurons, also act as part of the niche to affect

Frontiers in Cell and Developmental Biology | www.frontiersin.org 1 April 2017 | Volume 5 | Article 29 Liu and Jin The Interorgan Communication in Drosophila the steady state (Kux and Pitsouli, 2014). Likewise, neighbors adjust their performances based on gut-expressed signals. During the past few years, our comprehension of the mechanisms underlying organ-organ communication has expanded considerably. This review briefly summarizes the integrated molecular network regarding the links between the Drosophila GI tract and crucial neighbors, followed by a discussion of the potential value of these intriguing associations in fundamental biological processes, including the maintenance of homeostatic equilibrium.

AN OVERVIEW OF THE GI TRACT

The anatomical details of the adult Drosophila GI tract are relatively well known. The adult GI tract is traditionally divided into three discrete domains, the foregut, the midgut and the hindgut, containing the five best-understood stem cells related to turnover (Charroux and Royet, 2010; Zeng et al., 2013). Two studies have investigated sub-specialization to date (Buchon et al., 2013; Marianes and Spradling, 2013). The absorptive enterocytes (ECs) and secretory enteroendocrine cells (EEs) are the main cell types along the GI tract (Lucchetta and Ohlstein, 2012). A short and narrow segment, known as the copper cell region (CCR), is located in the middle (Li H. et al., 2016). Similar to adults, the larval midgut has three segments based on the acid-secreting middle segment (Shanbhag and Tripathi, 2009). The gastric cecum is a special segment that does not exist in the adult GI tract. Additionally, the level of cellular transport processes in the larval epithelium is higher than that in FIGURE 1 | Schematic of the Drosophila GI tract anatomy. (A) The adult adults (Shanbhag and Tripathi, 2009). Functional diversification GI tract is composed of three main parts: the foregut, the midgut, and the in subsections of the larval midgut has been analyzed by Harrop hindgut. The midgut includes three sections: the anterior midgut, the CCR, and the posterior midgut. (B) The larval GI tract structure is similar to that in adults. et al. (2014). A summary of the GI tract structures of both adults and larvae is provided in Figure 1. GI tract is surrounded by smaller tubes named tracheoles from GOOD NEIGHBORS the tracheal system, which is responsible for delivering oxygen to the epithelium and expelling carbon dioxide, achieving tissue gas The primary concern of studies investigating gut-neighbor axes exchange and meeting the oxygen needs of intestinal cells (Kux is to validate the existence of peripheral organs and tissues and Pitsouli, 2014). (6) The GI tract is surrounded by circular and that communicate with the GI tract. There is now substantial longitudinal visceral muscles (VMs), which facilitate the mixing, evidence suggesting that several non-gastrointestinal organs and grinding, and pushing forward of ingested food (Royet, 2011). tissues interact with the GI tract to ensure the optimal state of (7) Within the hemocoelic body cavity, there is an excretory and the organism, including the following: (1) One good neighbor osmoregulatory organ known as the Malpighian tubules (MTs), is the hemocytes, which are associated with the phagocytosis which perform a series of functions, such as excreting metabolic and encapsulation of invading pathogens. Only three types waste (Affolter and Barde, 2007). (8) Ovarian function and of differentiated cells, namely plasmatocytes, crystal cells and maintenance require multiple signals from peripheral organs. lamellocytes, can be distinguished (Meister, 2004; Crozatier and Each female has a pair of ovaries, and each ovary contains 15–20 Meister, 2007). (2) Sensing and responding to nutrients with the ovarioles that consist of a series of egg chambers (Kirilly and Xie, synthesis and release of energy are considered the function of the 2007). Other organs that signal to others include the lymph gland, “liver,” termed the fat body, which interacts with the GI tract to salivary gland, retina, skeletal muscles, and prothoracic gland. meet different physiological needs (Sousa-Nunes et al., 2011). (3) In the following, we will discuss recent evidence supporting the The enteric neurons that innervate the GI tract were summarized involvement of organ-to-organ communication strategies in the in a recent report showing the gastrointestinal roles of the regulation of organismal health. nervous system in the control of intestinal physiology (Kuraishi et al., 2015). (4) Of particular interest are the insulin-producing ORGAN-TO-ORGAN COMMUNICATION cells (IPCs) of the brain, which are thought to regulate growth, metabolism, and stress responses through the production of The first integrated ideas discussed in this review focus on the different insulin-like peptides (Dilps) (Nässel et al., 2013). (5) The fundamental principles concerning the links between organs

Frontiers in Cell and Developmental Biology | www.frontiersin.org 2 April 2017 | Volume 5 | Article 29 Liu and Jin The Interorgan Communication in Drosophila in adults, which correlate with the homeostatic regulation of other aspects of biological processes, such as intestinal physiology metabolism, physiology and aging and are currently under and metabolic processes. intense investigation. We will also discuss the larval aspects of interorgan communication. Although an exhaustive summary of Fat Body all the data in these fields would be impossible, this review will Study of signaling pathways involved in the fat body-gut highlight emerging trends. communication model is a fruitful research direction. A recent expansion of the literature has focused on gut-mediated metabolic homeostasis in the fat body. For example, according A TALE IN THE ADULT BODY CAVITY to Perrimon N and co-workers, the GI tract contains EEs, which secrete gut prohormones related to systemic lipid storage and Gut-Neighbor Axes metabolism (Song et al., 2014). Flies with loss of tachykinin (TK) Hemocytes EEs display an increased lipid level in the fat body. Starvation- First, we present the “state of the art” on the study of hemocyte- induced excess gut TK levels contribute to the loss of systemic gut communication models. Exploring the gut-hemocyte axis has lipid storage due to protein kinase A (PKA)-mediated Sterol been a recent focus of interest. Breakthrough discoveries include regulatory element-binding protein (SREBP) inhibition (Song the identification of hemocyte-expressed messages as dedicated et al., 2014). Additionally, Li et al. have characterized the function regenerative inflammatory factors that facilitate regeneration of neurotensin (NT) in the modulation of lipogenesis in the after intestinal damage. To understand the functional roles fat body (Li J. et al., 2016). An EE-expressed high NT level of hemocyte-gut communication, we need to consider the triggers increased lipid accumulation, which is accompanied by location of hemocytes within the adult body cavity. Indeed, decreased AMP-activated protein kinase (AMPK) activation (Li most hemocytes are concentrated within the middle of the J. et al., 2016). It will not be long before other EE-expressed midgut, several individual hemocytes also appear close to the signals are discovered, thus expanding the repertoire of links intestinal epithelium. Jasper H and co-workers have shed light between the intestinal endocrine system and systemic lipid on the temporal sequence of interactions between hemocytes and metabolism. Furthermore, these studies raise another interesting intestinal cells during pathogen infection (Ayyaz et al., 2015). question: Are EEs the only cell type associated with systemic Hemocyte-expressed Decapentaplegic (Dpp) triggers Saxophone lipid accumulation? An area of obvious interest might be the (SAX) and Smad on X (SMOX) activation in the epithelium relationship between EC-mediated nutrient uptake and systemic during the early phase of infection, contributing to intestinal homeostasis. Remarkably, a key trigger of lipid accumulation stem cell (ISC) proliferation; re-establishing ISC quiescence appears to be intestinal acidity, which was confirmed by an requires the activation of Thickvein (Tkv) and MAD. Adults interesting investigation of an obese-like phenotype suggesting with hemocyte loss are sensitive to infection (Ayyaz et al., that the level of lipid accumulation is down-regulated in flies with 2015). Further studies have rapidly progressed, spurred by intestinal acid suppression (Lin et al., 2015). Jasper H and co- Lemaitre B’s laboratory (Chakrabarti et al., 2016). Specifically, workers have addressed the complexity of several gut-expressed hemocyte-expressed Unpaireds (Upds) are relevant to ISC stress-protective genes with respect to metabolic homeostasis mitogenesis after infection, emphasizing a role for hemocytes (Biteau et al., 2010). The overexpression of heatshock protein in intestinal regeneration. It is notable that hemocyte-mediated 68 (hsp68) and jafrac1 in intestinal precursors results in the intestinal regeneration was thoroughly illuminated by the above suppression of metabolic decay. The importance of gut-expressed two reports, based on a model of the direct introduction signals in energy metabolism is particularly highlighted by two of bacteria into the enteric cavity. Therefore, it will be interesting studies. First, a recent finding identified a role of PGC- interesting to discover the cues by which the pathogen-infected 1 from the intestine in controlling this metabolic process (Rera intestine signals to hemocytes, contributing to its regeneration. et al., 2011). PGC-1 overexpression enhances mitochondrial Additionally, a recent study mapped the apoptotic caspase activity. Importantly, this causes significant increases in both the pathway in the intestine after systemic wounding (Takeishi amount of stored glycogen and free glucose levels, accompanied et al., 2013). Wounding-induced reactive oxide species (ROS) by a decrease in triglyceride (TAG) levels, supporting the role trigger apoptotic caspase pathway activation in ECs, which is of PGC-1 in maintaining energy homeostasis (Rera et al., 2011). responsible for suppressing the production of systemic lethal Second, according to Kohyama-Koganeya et al. systemic energy factors (Takeishi et al., 2013). Caspase activity loss in ECs homeostasis also depends on Bride of sevenless (BOSS) activity causes increased levels of systemic lethal factors in hemolymph, from neurons in the brain and EEs in the intestine (Kohyama- enhancing the sensibility of flies to non-infectious stresses Koganeya et al., 2015). Additionally, systemic antimicrobial (Takeishi et al., 2013). Together, these studies suggest that peptides (AMPs) are also affected by the intestinal immune hemocyte-gut communication acts as a critical strategy that response. The fat body secretes AMPs to directly remove regulates the response of ISCs to oral infection. Regrettably, no ingested pathogens. The levels of AMP expression in the fat tests are available to identify the roles of hemocyte-expressed body are associated with the gut-expressed PGRP-LE, which can signals in other intestinal actions. While significant progress has be suppressed by several gut-expressed amidase peptidoglycan- been made in establishing the potential mechanisms by which recognition proteins (PGRPs), such as PGRP-LB and PGRP- hemocytes regulate intestinal regeneration, in-depth analyses SCs (Paredes et al., 2011; Bosco-Drayon et al., 2012). Thus, we employing hemocytes are required to define correlations with suggest that the gut-fat body communication strategy controls

Frontiers in Cell and Developmental Biology | www.frontiersin.org 3 April 2017 | Volume 5 | Article 29 Liu and Jin The Interorgan Communication in Drosophila and regulates systemic AMP production, which, identical to et al., 2015). Dus et al. have shown that D-glucose-induced AMPs from the intestine, also contributes to defense against Dh44 activity in brain neurons, which is transmitted to R2 gut ingested pathogenic microorganisms (especially pathogens that cells, is responsible for intestinal motility and excretion (Dus are capable of crossing the intestinal epithelium). et al., 2015). However, many questions remain, including the Several groups have shown another critical strategy by which following: Are any other hormones from the brain responsible the fat body signals to the intestine, providing a potential for this intestinal action? If this is the case, how are these link between fat body-expressed factors and intestinal actions. hormones coordinated to adapt normal intestinal metabolic For example, Zheng and co-workers have demonstrated the levels to organ demands? Additionally, attempts have been made involvement of lamin-B from fat body cells in gut hyperplasia to analyze the neuropeptide-mediated meal size. Leucokinin during aging (Chen et al., 2014). Fat body-specific lamin-B receptor (Lkr) neurons in the brain innervate the foregut, and loss exacerbates immunosenescence, which contributes to the brain neuron-expressed leucokinin neuropeptide (Leuc) and Lkr deregulation of the immune deficiency (Imd) signaling pathway regulate total food intake (Al-Anzi et al., 2010). A role of in the intestinal epithelium, causing turnover loss (Chen et al., AMPK in autophagy has been detected in the brain and gut 2014). Interestingly, the nutrient-sensing pathways regulated by Ulgherait et al. who showed that AMPK overexpression by the fat body are indispensable for intestinal digestion and in the brain triggered autophagy and slowed intestinal aging absorption. Carbohydrase and lipase levels within the midgut (Ulgherait et al., 2014). This study also suggested that brain- are regulated by Dawdle (Daw) secreted from the fat body, expressed Autophagy-specific gene 1 (Atg1) activity is associated which activates its receptors Baboonc (Baboc) and Punt (Put) with the maintenance of intestinal homeostasis (Ulgherait et al., to reduce carbohydrase and lipase expression by enhancing the 2014). Taken together, these findings indicate that the strategy Smad2 level (Chng et al., 2014). Taken together, this series of brain-gut communication might be highly complex, and an of remarkable results suggests the roles of signals from the understanding of intestinal actions will require a more integrative fat body in controlling multiple aspects of intestinal actions, view of how these signals from the brain are allocated for different including aging-related intestinal inflammation and metabolic purposes. homeostasis. It is becoming increasingly apparent that the brain also adjusts its performance based on the response of the intestine Brain to changing nutritional conditions. Sano H has suggested that In the past few years, brain-to-gut communication models CCHamide-2 (CCHa2) in the intestine is clearly important for have been an area of intense investigation. Indeed, the brain this process (Sano, 2015). Nutrient-mediated CCHa2 controls has been described as the canonical organ for the production Dilp production in the brain by stimulating the level of its of Dilps, and it is now widely acknowledged that the brain receptor, CCHa2-R, supporting a molecular basis of the gut-brain directly affects intestinal immunity, physiology and metabolism axis for Dilp levels (Sano, 2015). A separate study has suggested (Nässel et al., 2013). Recently, several studies sought evidence of that the level of nutrient restriction-induced Limostatin (Lst) links between IPC-Dilps and gastrointestinal homeostasis. For from gut-associated endocrine corpora cardiaca (CC) cells, along example, it was shown that brain-expressed Dilp2 is essential with its receptor CG9918, is also involved in Dilp secretion for ISC self-renewal after damage (Amcheslavsky et al., 2009). in IPCs (Alfa et al., 2015). In addition to a direct influence Loss of brain-expressed Dilp2 caused an increased number of on the production of Dilps, other interesting aspects of gut- Phosphorylated-histone 3+ (PH3+) cells under inflammation, expressed signals have been documented. For example, according and the damage-induced epithelial layer of flies with systemic to Ulgherait et al., autophagy in the brain is regulated by gut- Dilp2 loss also became disorganized (Amcheslavsky et al., expressed AMPK activation (Ulgherait et al., 2014). In summary, 2009). However, the molecular architecture underlying this the reason for and consequence of this correlation between gut- Dilp-mediated intestinal regeneration is not well understood. expressed signals and Dilp production from the brain remain Interestingly, results obtained by Shen et al. have shown that enigmatic. Given that Dilp levels are strongly associated with cAMP response element-binding protein (CREB) and cAMP- metabolism, stress responses and lifespan, research into the regulated transcription coactivator (Crtc) from the brain are effects of signals from the GI tract on Dilp levels has advanced indispensable for intestinal energy homeostasis (Shen et al., our understanding of how the GI tract communicates with the 2016). The loss of short neuropeptide F (sNPF) in ECs induced brain to regulate organismal health. by CREB and Crtc suppression results in the deregulation of epithelial integrity, increased levels of AMPs and energy balance Enteric Neurons defect (Shen et al., 2016). An in-depth understanding of the role Only a few years ago, little was known with respect to enteric of traumatic brain injury (TBI) in intestinal barrier function has neuron-gut communication. However, in recent years, progress been confirmed by observations of increased bacteria, glucose has been made in this area such that there is now overwhelming and innate immune response levels following traumatic injury- evidence suggesting that enteric neurons exert far-reaching mediated death (Katzenberger et al., 2015). A recent study has effects on GI tract behavior (Cognigni et al., 2011). A direct role provided important insights into the roles of brain-expressed of enteric neurons in intestinal physiological homeostasis was hormones in intestinal metabolism, suggesting that the level confirmed by an interesting study in which neuronal (Hedgehog) of nutritive sugar-mediated Diuretic hormone 44 (Dh44) in Hh loss triggered a defect in janus kinase/signal transducer the brain influences intestinal ingestion and digestion (Dus and activator of transcription (JAK-STAT) signaling pathway

Frontiers in Cell and Developmental Biology | www.frontiersin.org 4 April 2017 | Volume 5 | Article 29 Liu and Jin The Interorgan Communication in Drosophila levels, leading to the deregulation of EC fate determination intestinal growth in newly eclosed flies (Amcheslavsky et al., (Han et al., 2015). However, the exact mechanisms involved 2014). The role of VM-specific signals in ISC proliferation in neuronal Hh-mediated intestinal homeostasis have not been through EEs has been revealed by another study. Paracrine assessed to date. Future experiments should focus on the Bursicon (Burs) from EEs with its receptor Drosophila leucine- question of how neuronal Hh interacts with the JAK-STAT rich repeat-containing G protein-coupled receptor 2 (DLGR2) signaling pathway to regulate EC differentiation. Recent studies reduces the Vein (Vn) level by stimulating cyclic AMP (cAMP) investigating the gut-to-enteric neuron communication model activation in VM, which influences ISC proliferative activity have yet to unravel the roles of enteric neurons in multiple and intestinal homeostasis (Scopelliti et al., 2014). Although the physiological functions. Growing evidence gleaned by Olds WH major focus of research on VM-gut communication models has and Xu T has suggested that the loss of PPK1 in posterior enteric been in the context of the response of ISC proliferative activity neurons reduces food intake levels through mechanosensory ion to VM-expressed signals, there is now a growing emphasis channels (Olds and Xu, 2014). According to Kenmoku et al., on studying VM-mediated altered modes of ISC division. The the maintenance of barrier function is causally linked to a contribution of a shift in stem cell behavior in tissue remodeling specific subset of enteric neurons innervating the anterior midgut has been reported by Bilder D and co-workers. VM-specific (Kenmoku et al., 2016). The peritrophic matrix and epithelial Dilp3 and systemic Dilp2, 5 drive intestinal growth through ISC barrier of flies with loss of activity of these enteric neurons symmetric division in freshly eclosed flies after food ingestion display high permeability (Kenmoku et al., 2016). Taken together, (O’Brien et al., 2011). Taken together, these findings suggest these findings suggest that this neuron-gut communication that despite significant evidence supporting the mechanical strategy has far-reaching effects on the regulation of intestinal regulation of ISC actions by VM, the next big challenge is how regeneration and physiology. However, many questions about the signals secreted from VM affect intestinal physiological and the link between the intestine and enteric neurons remain. For metabolic homeostasis. example, can the intestine signal to enteric neurons? If so, how do gut-expressed factors regulate the enteric nervous system? Intestinal Trachea, Ovary, Body Muscle, and MT It is becoming increasingly clear that the recognition of signals Visceral Muscle (VM) from the intestinal trachea may be a strategy that largely Research investigating the links between VM and the intestine controls intestinal regeneration and homeostasis. A remarkable has clearly progressed at an impressive rate over the last few discovery in the gut-to-trachea communication model by Lin years. The primary concern of studies investigating the molecular X and co-workers has suggested that trachea-expressed Dpp is mechanisms regarding VM-to-gut communication is to validate highly correlated with midgut homeostasis, underscoring the the roles of VM-expressed messages in ISC activity under importance of roles of the intestinal trachea in ISC proliferation physiological homeostasis and under stress conditions. In this (Li Z. et al., 2013). However, the role of trachea-expressed section, we will focus on depicting a high-resolution picture of Dpp in intestinal homeostasis and regeneration is extremely mitogenic signals from VM. According to Xi R and co-workers, controversial. Indeed, Dpp expression appeared in the intestinal VM acts as an ISC niche to secrete signals affecting ISC activity trachea of unchallenged flies and was strongly induced in the and intestinal homeostasis (Lin et al., 2008). Loss of wingless intestinal trachea after injury (Guo et al., 2013; Li Z. et al., (wg) in VM reduces the Notch level in the intestine, causing 2013). Recent data have suggested that the loss of trachea- defects in ISC proliferation and differentiation; on the contrary, expressed Dpp has no effect on impaired BMP levels in ISCs flies with wg overexpression in VM display excessive ISC-like and their proliferative activity after intestinal damage (Guo et al., cells (Lin et al., 2008). Agaisse H and co-workers investigated 2013). Why does this phenomenon occur? There are at least the role of the VM-expressed JAK-STAT signaling pathway two possibilities. (1) The simplest explanation would be that in the stimulation of ISC division in response to challenge injury triggers the extensive activation of multiple signaling (Zhou et al., 2013). Infection-induced Upd3 in ECs activates pathways (such as the epidermal growth factor receptor (EGFR) the JAK-STAT signaling pathway in VM, which is responsible and JAK-STAT pathways) that can sufficiently regenerate the for ISC division by secreting the ligand Vn (Zhou et al., 2013). intestinal epithelium, but trachea-expressed Dpp is a secondary Additionally, similar to the influence of hemocyte-expressed Dpp mitogenic signal at this moment. (2) We do not know how on intestinal regeneration after infection, Dpp has been shown Dpp is transmitted from the trachea to the intestine. Thus, to be expressed in VM using a Dpp-LacZ line, maintaining despite an increased Dpp level after the ingestion of reagents bone morphogenetic protein (BMP) signaling in the midgut (such as paraquat), we speculate that injury also causes serious and regulating intestinal homeostasis (Guo et al., 2013; Zhou defects in tracheal activity, which might contribute to preventing et al., 2015). In addition to VM, ECs act as a niche to control the transformation of the trachea to the intestine. The nature homeostasis and damage-induced regeneration. For example, of the signaling pathways responsible for this trachea-gut several studies have revealed a key role of EC-expressed Dpp communication model is still unknown, and an understanding of in lineage differentiation, especially copper cell differentiation, how trachea-expressed Dpp is integrated into the intestine under under physiological homeostasis (Li H. et al., 2013; Tian and homeostasis and inflammation are among future challenges. It Jiang, 2014). An important link between diet and Dilp production is anticipated that the influence of trachea-expressed signals on in VM was established by Amcheslavsky et al., who suggested intestinal actions will be manifold (they might contribute to that nutrient-stimulated TK activity in EEs is associated with intestinal physiology and metabolism) and is only starting to VM-specific Dilp3 secretion, contributing to ISC division and be understood. Furthermore, the roles of gut-expressed signals

Frontiers in Cell and Developmental Biology | www.frontiersin.org 5 April 2017 | Volume 5 | Article 29 Liu and Jin The Interorgan Communication in Drosophila in tracheal actions remain enigmatic. In consideration of the axes in adult Drosophila. The influences of these neighbor- aforementioned notion that Dpp from VM and EC plays an neighbor communication strategies on different biological important role in intestinal regeneration, these models raise two aspects will be discussed in detail. additional important questions regarding why the same factor from different niches (such as the VM, intestinal trachea and Reproductive Behaviors ECs) regulates similar biological processes and how an ISC senses Research into how precise mechanisms regulate stem cell activity specific Dpp signals from different niches to affect intestinal has been most extensively conducted in reproductive systems, yet homeostasis. much is still unknown regarding how signals from other organs Next, this review will focus on the gut-ovary/body muscle achieve this process. The greatest progress in our knowledge axes. Recently, Perrimon and co-workers has shown that systemic of the extrinsic factors regulating reproductive behavior has organ wasting is related to the level of ISC proliferation. ImpL2 come from studies of Dilps from the brain, which are strongly secreted from the intestine with yorkie (Yki) loss reduces associated with germline stem cell (GSC) proliferation. Ikeya systemic insulin/insulin-like growth factor (IGF) signaling, et al. established a causal link between female GSC proliferative establishing ovary, muscle and fat body wasting (Kwon et al., activity and brain-expressed Dilp levels. Defects in brain- 2015). A role of juvenile hormone (JH) signaling has been expressed Dilp activity are strongly associated with the loss of proposed in the regulation of mating-mediated intestinal egg production (Ikeya et al., 2002). In support of this model, remodeling. Intestinal remodeling in females is regulated by the Liu et al. suggested that ovarian maturation in the first days JH, Methoprene-tolerant (Met) and Germ cell-expressed (Gce) of adult life can be regulated by brain-expressed Dilp1 (Liu receptors after mating, which drives reproductive remodeling et al., 2016). Additionally, a previous study reported that IPC- (Reiff et al., 2015). Additionally, it should be noted that intestinal expressed Dilps control GSC division and vitellogenesis (LaFever AMPK activation regulates muscle homeostasis during aging and Drummond-Barbosa, 2005). Flies with IPC loss have (Ulgherait et al., 2014). Taken together, these findings support severely impaired follicle cell proliferation ability in response to the notion that gut-expressed signals appear to be responsible for nutritional input. Several factors cooperate with IPC-expressed body muscle and ovary behaviors. Dilps to affect the reproductive system. For example, a recent Intriguingly, the basic biological processes of the renal system study implicated a role of brain-produced Drosophila alpha- are also regulated by intestinal behaviors. The observation that endosulfine (dendos) protein in normal rates of egg chamber gut-expressed signals cooperate with their receptors within the development and follicle cell proliferation by regulation of Dilp MTs to affect renal function was made by Talsma et al., who levels (Drummond-Barbosa and Spradling, 2004). Dendos loss in revealed the myotropic effects of pigment-dispersing factor the brain causes a defect in the proliferative response of ovarian (PDF), a central neuropeptide PDF (Talsma et al., 2012). cells to nutritional changes (Drummond-Barbosa and Spradling, Intestinal PDF activates its receptor, PDF receptor (Pdf-R), which 2004). A fat body-ovary axis with respect to GSC status has been is expressed by muscles in the MTs to control ureter contractions reported. Target of Rapamycin (TOR) activation in the fat body by enhancing cAMP activity (Talsma et al., 2012). Additionally, is triggered by high amino acid levels, which plays an important Nässel DR and co-workers presented evidence that gut-expressed role in GSC maintenance and ovulation rates; however, lower TK, as a circulating hormone, triggers Dilp5 activation in the amino acid levels cause increased GCN2 kinase activity in the fat principal cells from MTs through the TK receptor (TK-R) to body, leading to GSC loss (Armstrong et al., 2014). In summary, affect stress resistance (Söderberg et al., 2011). This finding was reproductive behaviors thus seem to be caused by a large number confirmed by the observation of increased survival under stress of systemic changes that influence GSC maintenance and self- of TK-R, Dilp5 and Drosophila insulin receptor (dInR) mutants renewal. (Söderberg et al., 2011). Although existing data indicate that gut-expressed signals are important regulators of MT behaviors, Stress Resistance and Lifespan it remains largely unknown whether these signals coordinate There is growing recognition that brain-to-fat body MT-expressed signals with the emergence of nephropathy. A communication is involved in stress resistance and lifespan. summary of the information relevant to gut-neighbor axes in First, we provide several interesting findings with respect to the adults is presented in Figure 2 and Table 1. To date, most of roles of several communication strategies stress responses. For our knowledge about peripheral organs associated with adult example, Bai et al. suggested that the Dilp6 level in the fat body is intestinal actions comes from the brain and fat body. Many points deeply involved in the regulation of brain-expressed Dilp2, 5 (Bai need to be further clarified to understand the intestinal actions et al., 2012). Fat body-expressed Dilp6 overexpression increases caused by signaling pathways from other peripheral organs, the level of transcriptional target of dFOXO, which triggers including the intestinal trachea and enteric neurons. decreased activity of hemolymph Dilp2 and brain-expressed Dilp2, 5, contributing to improving oxidative stress resistance and extending lifespan (Bai et al., 2012). According to Bauer NEIGHBOR-NEIGHBOR AXES et al., the reduced Dilp2 and insulin signaling levels in the fat body are thought to be mediated through the dysfunction Attempts to underscore the relationships between peripheral of IPC-expressed Drosophila melanogaster p53 (Dmp53), organs are currently underway. In this section, we review accompanied by lifespan extension (Bauer et al., 2007). The key emerging data supporting the existence of neighbor-neighbor role of IPC-expressed jun-N-terminal kinase (JNK) activity in

Frontiers in Cell and Developmental Biology | www.frontiersin.org 6 April 2017 | Volume 5 | Article 29 Liu and Jin The Interorgan Communication in Drosophila

FIGURE 2 | Diagram of interorgan communication in adults. The multifaceted molecular foundations underlying communication play a central role in the peaceful coexistence of organs, contributing to the maintenance of organismal health. Different types of organ-organ communication axes are color coded as follows: red and blue indicate gut-neighbor axes and neighbor-neighbor axes, respectively, and green indicates unknown axes. The relevant signals are exhibited and detailed descriptions are shown in Tables 1, 3. an organism’s stress response was confirmed by a recent report Next, the alteration of lifespan appears to involve an showing that the repression of Dilp2 triggered by IPC-expressed imbalance of communication between organs. According to JNK activation resulted in reduced insulin signaling levels in Demontis F and Perrimon N, muscle-expressed FOXO, and the periphery, such as the fat body, which is responsible for 4E-BP activity mitigates the loss of proteostasis in the aging increasing stress tolerance (Karpac et al., 2009). Taken together, retina, brain and fat body (Demontis and Perrimon, 2010). these findings show that brain-to-fat body communication FOXO and 4E-BP achieve these outcomes by triggering insulin strategy is crucial for stress responses, and deregulation of release and stimulating 4E-BP activity in other tissues (Demontis this strategy has important deleterious consequences for stress and Perrimon, 2010). One finding on AMPK activity was that resistance. AMPK overexpression in the brain induces autophagy, which

Frontiers in Cell and Developmental Biology | www.frontiersin.org 7 April 2017 | Volume 5 | Article 29 Liu and Jin The Interorgan Communication in Drosophila

TABLE 1 | Summary of the gut-neighbor axes in adults. is responsible for slowing muscle aging and prolonging lifespan (Ulgherait et al., 2014). Additionally, injury-induced Upd3 Neighbors Signals Comments Sources activity in hemocytes by the JNK signaling pathway stimulates the He JNK, Upd3, JAK-STAT Intestinal renewal Chakrabarti et al., level of JAK-STAT signaling in the fat body to promote survival of 2016 flies, suggestive of a hemocyte-to-fat body communication model He Dpp/TKV/MAD, Intestinal renewal Ayyaz et al., 2015 (Chakrabarti et al., 2016). The exact mechanisms that determine SAX/SMOX the organ-organ communication associated with lifespan are not IT Dpp Intestinal renewal Li Z. et al., 2013 yet known, but understanding this is evidently key to learning FB TK, PKA/SREBP Physiology, Song et al., 2014 precisely how lifespan is regulated, at least in the adult Drosophila metabolism model. FB Boss Physiology, Kohyama-Koganeya metabolism et al., 2015 Metabolic Homeostasis FB PGRP-LE Immune response Bosco-Drayon et al., 2012 Several studies have further explored organ-organ FB PGRP-SCs, PGRP-LB Immune response Paredes et al., 2011 communication models associated with metabolic homeostasis. FB lamin-B, Imd pathway Intestinal renewal Chen et al., 2014 For example, a recent study implied a role of fat body-expressed FB Daw, Baboc, Punt, Physiology, Chng et al., 2014 Dilp6 in starvation tolerance. Fat body-expressed Dilp6 TGF-b/Activin metabolism stimulates insulin-signaling activity in oenocytes, which is FB NT Physiology, Li J. et al., 2016 critical for lipid turnover in response to fasting (Chatterjee metabolism et al., 2014). It was shown that feed-mediated Upd2 production EN Hh, JAK-STAT Intestinal renewal Han et al., 2015 in the fat body activates the JAK-STAT signaling pathway EN ovo, SP, Leucokinin, Physiology, Cognigni et al., 2011 from GABAergic neurons innervated in IPCs to trigger the Dilp2, Dilp7 metabolism release of Dilps in the brain, which have the capacity to control EN NP3253 Intestinal Kenmoku et al., 2016 structure energy balance and systemic growth (Rajan and Perrimon, EN PPK1 Absorption, Olds and Xu, 2014 2012). Interestingly, considering the role of fat body-brain digestion communication strategies in improving oxidative stress EN PDF, PdfR, cAMP Excretion Talsma et al., 2012 resistance and extending lifespan described above, we suggest Br Dilp2, InR Intestinal renewal Amcheslavsky et al., that the same organ-organ communication model might be 2009 associated with different aspects of biological processes. Taken Br Crtc, CREB, sNPF Immune Shen et al., 2016 together, these findings suggest that the cues associated with response, stress the brain-fat body axis might be more than just a means of resistance understanding how these two organs collaborate to regulate Br AttC, DiptB, Mtk Intestinal Katzenberger et al., permeability 2015 metabolic homeostasis. This raises the real possibility that Br Dh44 Absorption, Dus et al., 2015 a dysfunctional interorgan communication network might digestion, contribute to the emergence of metabolic diseases. A summary excretion of the neighbor-neighbor axes in adults is provided in Figure 2 Br CCHa2,CCHa2-R, Physiology Sano, 2015 and Table 3. Dilps Br AMPK, Atg1 Intestinal Ulgherait et al., 2014 autophagy, LINKS BETWEEN LARVAL ORGANS homeostasis. Br Lst, Dilps Metabolism Alfa et al., 2015 Thus far, we have discussed data substantiating the notion that Br Leuc, Lkr Food intake Al-Anzi et al., 2010 dialogs between organs are essential processes in the life of Br JNK, Dilp2 Stress response Karpac et al., 2009 adult Drosophila, involving the maintenance and regulation of BM AMPK Muscle Ulgherait et al., 2014 homeostasis, reproductive behavior, stress resistance, lifespan, homeostasis and other process. Although our understanding of organismal Ov, FB, Yki, Imp-L2, Insulin/IGF Tissue wasting Kwon et al., 2015 development and growth is most highly advanced in larvae, there BM is still much to be learned about interorgan communication at VM Dpp Intestinal renewal Guo et al., 2013; Zhou this developmental stage. In this part of the review, we focus et al., 2015 VM Wg Intestinal renewal Lin et al., 2008 specifically on depicting a high-resolution picture of organ-to- VM TK, Dilp3 Intestinal renewal Amcheslavsky et al., organ communication models in larvae. 2014 VM Bur, DLGR2, cAMP, Vn Intestinal renewal Scopelliti et al., 2014 Gut-Neighbor Communication Models VM Dilp3 Intestinal renewal O’Brien et al., 2011 Fat Body and Prothoracic Gland VM Upd3, JAK-STAT, Intestinal renewal Zhou et al., 2013 We first emphasize the functional contribution of the gut-fat Vn/EGFR body axis. Hemocytes act as effective mediators that are pivotal MT TK, TKR, Dilp5, InR Stress resistance Söderberg et al., 2011 in the communication between gut-expressed ROS/nitric oxide MT PDF, PdfR, cAMP Renal function Talsma et al., 2012 (NO) and fat body-expressed AMP production. The Diptericin

He, hemocyte; IT, intestinal trachea; FB, fat body; EN, enteric neuron; Br, brain; BM, body (Dpt) level in the fat body is affected by the intestinal NO muscle; Ov, ovary; VM, visceral muscle; MT, malpighian tubule. activity triggered by ROS (Wu et al., 2012). Glittenberg et al.

Frontiers in Cell and Developmental Biology | www.frontiersin.org 8 April 2017 | Volume 5 | Article 29 Liu and Jin The Interorgan Communication in Drosophila presented evidence of the ability of pathogen and gut signals et al., 2015). They also found that these CCHa2 inactivation- to communicate with the fat body, leading to the activation induced defects might be due to the decreased Dilp2, 3 of systemic Toll-dependent immunity (Glittenberg et al., 2011). levels (Ren et al., 2015). Thus, these studies suggest that Candida-produced secreted aspartyl protease 4 (SAP4) and SAP6 CCHa2 acts as a key signal in brain to be clearly critical for and gut-produced NO contribute to Drosomycin (Drs) secretion regulation of gut nutrient uptake and developmental timing. from the fat body (Glittenberg et al., 2011). These findings suggest Interestingly, brain–gut axis is not only essential for food intake that a consequence of the loss of gut-expressed signals is a but also important strategy that control intestinal motility. defect in systemic immune responses, yet the exact mechanisms For example, four serotonergic neurons in the brain have responsible for gut-mediated systemic immune defects have yet been characterized by Schoofs et al., who suggested that to be investigated. Additionally, one recent study implicated central serotonergic neurons, as a conduit, play an important Gp93 as an effective regulator of intestinal function and lipid role in movements of the esophagus and proventriculus, catabolism (Maynard et al., 2010). Flies missing Gp93 display establishing a brain–gut neural pathway involved in foregut several defects in the midgut, accompanied by insulin loss and motility (Schoofs et al., 2014). We suggest that, like CCHa2, greatly enhanced fat body lipid catabolism (Maynard et al., these neurons could be implicated in regulation of intestinal 2010). absorption. Taken together, these studies illustrate how the Of particular interest is the prothoracic gland, which also brain–gut communication strategy impinges on larval food adjusts its performance based on the signals from gut. To date, intake. two studies have analyzed the intestinal actions that mediate Gut-expressed factors also regulate the actions of other signaling levels in the prothoracic gland. Hh appears to be a peripheral organs, such as the MTs and imaginal discs. A gut-expressed factor that possesses the ability to couple nutrition tantalizing study has shown that, in both larvae and adults, the to growth and developmental progression (Rodenfels et al., Diuretic hormone 31 receptor (DH31-R) and Diuretic hormone 2014). Tissue growth is regulated by circulating Hh that signals 44 receptor (DH44-R) signaling pathways in neurons of the to the fat body. Ecdysteroid production in the prothoracic central nervous system (CNS) and MTs are activated by the gland is also controlled by gut-expressed Hh, contributing to gut peptides DH31 and DH44 by triggering cAMP activation developmental timing (Rodenfels et al., 2014). Additionally, (Johnson et al., 2005). Furthermore, the receptor component modulatory control of prothoracic gland behavior also occurs protein (RCP) is utilized by DH31-R (Johnson et al., 2005). One through the actions of intestinal symbiotic bacteria. Research issue remains, however—the further outcome of gut-expressed investigating the role of Lactobacillus plantarum, an intestinal hormones on MT actions. Additionally, the field of interorgan commensal bacterium, in systemic growth has shown that gut- communication in larvae is currently attracting renewed interest, resident Lactobacillus plantarum (L. plantarum) triggers TOR especially concerning the influence of gut-expressed signals on activation in the fat body and prothoracic gland upon nutrient the wing imaginal disc. For example, a recent study investigating scarcity, which contributes to optimal development through organ lipid transport has shown that the neutral and polar lipid Dilps and ecdysone secretion from the brain and prothoracic composition of the brain and wing imaginal disc is controlled by gland, respectively, supporting an interesting link between this the mobilization of gut-produced lipid through Lipid Transfer intestinal commensal bacterium and hormonal growth signal Particle (LTP) and lipoprotein Lipophorin (Lpp) activation in production (Storelli et al., 2011). Therefore, the gut-prothoracic the fat body (Palm et al., 2012). This result suggest that there is gland communication strategy is thought to be a novel a lipid transport channel linking intestinal lipid levels and lipid contributor to the regulation of larval development. Increased composition of the brain and wing imaginal disc in larvae. emphasis is also being placed on the role of corpora allata- prothoracic gland communication strategy in development, Enteric Neurons and VM which will be discussed below. However, how the dialog between A novel cell type that communicates with the GI tract in the prothoracic gland and other organs is established remains an larvae was recently revealed: the enteric neurons. A fascinating intriguing question. study investigating the regulation of defecation behavior has suggested a link between enteric neurons and intestinal muscle Brain, MT, and Imaginal Discs (Zhang et al., 2014). The motor neurons innervating the Research on signaling crosstalk between the brain and intestine hindgut and anal sphincter cooperate with the intestinal muscle has seen impressive advances in the past few years. A novel to control defecation activity (Zhang et al., 2014). Although signal CCHa2, which is discussed above for its role in regulating striking advances have been made in recent years, the exact Dilp levels in adult brain, has also been found to be an regulatory network of links between enteric neurons and the important component of brain–gut signaling pathway in larvae. intestine is only partly understood. This is probably due to For example, Li et al. reported the exciting observation that the complexity of the signaling pathways responsible for this the brain receives feed-induced CCHa2 from gut endocrine communication model. Additionally, Bland et al. presented data cells through its receptor (Li S. et al., 2013). Furthermore, revealing the regulation of peristalsis through AMPK activity another study by Ren et al. has shown that food intake is from VM, contributing to intestinal function and organismal regulated by CCHa2 in larval brain (Ren et al., 2015). Because growth (Bland et al., 2010). However, contrary to the abundant flies with a dysfunction in CCHa2 show a significantly reduced contributions of VM-gut communication in adults, functional food intake and have a remarkably delayed development (Ren impacts of this communication strategy in larvae are still poorly

Frontiers in Cell and Developmental Biology | www.frontiersin.org 9 April 2017 | Volume 5 | Article 29 Liu and Jin The Interorgan Communication in Drosophila understood. Evidence uncovering the other signals from VM Non-Gastrointestinal Organ that regulate intestinal function should be available in the Communication Axes near future. Details of gut-neighbor communication models in Tissue Growth larvae are summarized in Figure 3 and Table 2. This review The influence of interorgan communication axes on tissue next summarizes numerous studies that have investigated well- growth has long been of interest and is being actively investigated established non-gastrointestinal organ communication models in in larvae. For example, growing evidence gleaned from several larvae acting as dedicated strategies regulating multiple aspects of studies has suggested the regulation of tissue growth by the brain- tissue growth, stem cell actions, development and other biological fat body axis. We outline the current data on this communication processes. model below. First, the putative involvement of brain-expressed

FIGURE 3 | Diagram of interorgan communication in larvae. Similar to adults, the signaling network necessary for interorgan communication ensures a steady state in the larval body cavity. Red and blue indicate gut-neighbor axes and neighbor-neighbor axes, respectively; green indicates unknown axes. The relevant signals are exhibited and detailed descriptions are shown in Tables 2, 3.

Frontiers in Cell and Developmental Biology | www.frontiersin.org 10 April 2017 | Volume 5 | Article 29 Liu and Jin The Interorgan Communication in Drosophila

TABLE 2 | Summary of the gut-neighbor axes in larvae. TABLE 3 | Summary of the neighbor-neighbor axes.

Neighbors Signals Comments Sources Axes Signals Comments Sources

He, FB NO, Dpt Immune response Wu et al., 2012 FB—BrA Upd2, JAK- Organismal growth, Rajan and Perrimon, EN nompC Defecation Zhang et al., 2014 STAT, Dilps metabolism 2012 A Br CCHa2 Metabolism Li S. et al., 2013 FB—Ov TOR, GCN2 Reproduction Armstrong et al., 2014 A Br CCHa2 Food intake Ren et al., 2015 He—FB JNK, Upd3, – Chakrabarti et al., JAK-STAT 2016 Br – Intestinal motility Schoofs et al., 2014 FB—BrA Dilp2, 5, 6 Lifespan Bai et al., 2012 VM AMPK Peristalsis, Bland et al., 2010 A organismal growth Br—FB Dmp53, Dilp2 Lifespan Bauer et al., 2007 A Br, MT DH31, DH44 Neural, renal function Johnson et al., 2005 Br—FB JNK, Dilp2 Stress response Karpac et al., 2009 A FB, Br, WID LTP, Lpp Metabolism Palm et al., 2012 Br—Ov Dilp1 Reproduction Liu et al., 2016 A FB, PG Hh Development, Rodenfels et al., 2014 Br—Ov Dilps Reproduction LaFever and organismal growth Drummond-Barbosa, 2005 FB, Br, PG TOR, Dilps, Organismal growth Storelli et al., 2011 A ecdysone Br—Ov dendos Reproduction Drummond-Barbosa and Spradling, 2004 FB NO Immune response Glittenberg et al., 2011 Br—BMA AMPK Muscle homeostasis Ulgherait et al., 2014 FB Gp93 Metabolism Maynard et al., 2010 Br—OvA Dilps Reproduction Ikeya et al., 2002 He, hemocyte; FB, fat body; EN, enteric neuron; Br, brain; VM, visceral muscle; MT, BM—Re, Br, FOXO, 4E-BP, Proteostasis Demontis and malpighian tubule; WID, wing imaginal disc; PG, prothoracic gland. FBA Insulin Perrimon, 2010 EN—ITL PDF, Dilp7, Tissue growth Linneweber et al., Dilp2,3,5 2014 Dilps and fat body-expressed insulin in larval tissue growth FB—BrL TORC1, Dilps Metabolism Géminard et al., 2009 has been evaluated by several interesting reports. For example, FB—BrL dMyc, Dilp2 Organismal growth Parisi et al., 2013 Lee et al. showed that sNPF and sNPF receptor 1 (sNPFR1) FB—BrL mitogen CNS Britton and Edgar, stimulate Dilp2 activity through the regulation of extracellular 1998 signal-related kinases (ERK) in IPCs (Lee et al., 2008). Secreted FB—BrL Slif, InR, PI3K/ CNS Sousa-Nunes et al., Dilp2 acts as a key regulator to affect insulin signaling levels in TOR 2011 the fat body, which is strongly related to growth and metabolism. Br—FBL sNPF, SNPFR1, Organismal growth, Lee et al., 2008 Furthermore, the influence of fat body-expressed Drosophila Dilp2 metabolism Myc (dMyc) on organismal growth has been shown by Parisi Br—POL SDR, Dilps, Tissue growth Okamoto et al., 2013 et al., who suggested that dMyc activity from the fat body is Insulin/IGF responsible for the release of Dilp2 from the brain, contributing FB, Br—LGL Dilp2, Hematopoiesis Shim et al., 2012 to the systemic increase in size (Parisi et al., 2013). In an InR-dTOR-wg L interesting model presented by Okamoto et al., glia-expressed FB—SG Slif, TSC/TOR, PI3 Tissue growth Colombani et al., 2003 secreted decoy of InR (SDR) binding to circulating Dilps affects BM—SG, InR, Foxo, dMyc Tissue growth Demontis and FBL Perrimon, 2009 insulin/IGF signaling activity in peripheral organs, contributing Br—PGL Imp-L2, IIS Development Sarraf-Zadeh et al., to organismal growth (Okamoto et al., 2013). The faster rate is 2013 triggered by SDR loss-induced increased insulin levels, thereby He—BML Upd2, Upd3 Immune response Yang et al., 2015 leading to increased body size. According to Léopold P and CA—PGL JH, Insulin, Development, Mirth et al., 2014 co-workers, a humoral signal is released into the hemolymph ecdysone organismal growth through TOR signaling pathway in the fat body to stimulate FB—BrL Eiger, TACE, Grnd Organismal growth Agrawal et al., 2016 the secretion and accumulation of Dilps in IPCs (Géminard FB—HtL TOR Heart structure, Birse et al., 2010 et al., 2009). All of these observations demonstrate that brain-to- function fat body communication strategy control larval growth through BM—FBL Imp-L2 Lifespan Owusu-Ansah et al., Dilps and insulin signals. Second, other signals from the brain 2013 and fat body are also associated with this biological process. FB, fat body; Br, brain; Ov, ovary; He, hemocyte; BM, body muscle; Re, retina; IT, intestinal For example, Agrawal et al. argued that TNF-α converting trachea; EN, enteric neuron; PO, peripheral organ; LG, lymph gland; SG, salivary gland; enzyme (TACE)-mediated Eiger (Egr) secretion from the fat body PG, prothoracic gland; CA, corpora allata; Ht, heart; A, adults; L, larvae. contributes to organismal growth through Grindelwald (Grnd) activity in the brain in response to a normal protein diet (Agrawal et al., 2016). pathway in larval skeletal muscles was suggested following the Additionally, our current knowledge of organ-organ discovery that InR/Foxo-induced dMyc transcriptional activity communication models responsible for salivary gland growth in muscles affects the growth of muscles and other peripheral is rudimentary. To date, two studies have investigated the tissues, such as the salivary glands and fat body, suggesting a well-established regulators that largely control salivary gland requirement for InR-Foxo-dMyc for the size of skeletal muscles growth. A functional role for the InR-Foxo-dMyc signaling and other tissues (Demontis and Perrimon, 2009). Additionally,

Frontiers in Cell and Developmental Biology | www.frontiersin.org 11 April 2017 | Volume 5 | Article 29 Liu and Jin The Interorgan Communication in Drosophila a question pertaining to the global growth of fat body control has target of this channel. For example, according to Britton and been solved by Colombani et al. Slimfast (Slif) loss in the fat body Edgar, a novel mitogen from the fat body is deeply involved in causes a dysfunction in tuberous sclerosis complex (TSC)/TOR the proliferative activity of NBs in the larval CNS (Britton and signaling, leading to the inhibition of salivary gland growth Edgar, 1998). Sousa-Nunes et al. suggested that the fat body- induced by phospho-inositide 3-kinase (PI3K) inactivation specific activation of Slif, InR and PI3K/TOR causes NBs to exit (Colombani et al., 2003). The above examples of the regulation quiescence (Sousa-Nunes et al., 2011). Dilps from glial cells are of salivary gland growth caused by signals from skeletal muscles required for NB reactivation, supporting a role of fat body-glia- and the fat body beg the following questions: What are the NB relay in proliferation. A link between NBs and glial cells consequences of changes in salivary gland growth? In addition has been reported by another study showing that Dilp secretion to signals from these two organs, can we identify circulating from glial cells stimulates PI3K/Akt levels in NBs, which drives signals from other peripheral organs that control salivary gland NB proliferation (Chell and Brand, 2010). Taken together, most behavior? studies of cross-talk-associated stem cell actions to date have been Several uncommon interorgan communication models have centered on the regulation of neural stem cells in the larval brain. recently been elucidated. As mentioned above, two studies have Future studies will focus on exploring the further consequences identified gut-expressed signals as being of critical importance in of cross-talk-mediated alteration of NB proliferative capacity. regulating prothoracic gland actions and contributing to tissue growth (Storelli et al., 2011; Rodenfels et al., 2014). Interestingly, Development in addition to the gut-prothoracic gland communication strategy, Understanding how interorgan communication contributes signals from other specific organs are essential for tissue growth to larval development is a challenging and fundamental by regulating prothoracic gland actions. For example, the question. Recently, the brain and prothoracic gland have been insulin-dependent regulation of tissue growth by JH release thought to be the two main organs participating in the was demonstrated in the corpora allata (Mirth et al., 2014). regulation of development. Data obtained from Sarraf-Zadeh Experiments have shown that flies lacking corpora allata- et al. indicated a local function of Imaginal morphogenesis expressed JH have decreased levels of insulin signaling caused by protein-Late 2 (Imp-L2) in developmental timing (Sarraf- ecdysone synthesis in the prothoracic gland, leading to a defect Zadeh et al., 2013). Brain ring gland-expressed Imp-L2 in body size (Mirth et al., 2014). Additionally, Linneweber et al. regulates developmental timing through insulin-growth-factor- functionally linked tracheal cellular growth to enteric neuron like signaling (IIS) activity in the prothoracic gland. Loss of Imp- activity, providing strong evidence supporting the regulation of L2 accelerates development, but Imp-L2 overexpression delays terminal cell growth in the posterior tracheal branches by Dilp7- pupariation (Sarraf-Zadeh et al., 2013). The work of Layalle and PDF-Gal4-positive neurons innervated around the hindgut et al. revealed a function of the TOR signaling pathway in via insulin signaling based on metabolic status (Linneweber et al., the prothoracic gland in developmental timing (Layalle et al., 2014). Taken together, these findings suggest that, to maintain 2008). The reduced ecdysone level in the prothoracic gland healthy regulation of tissue growth, harmonious coordination induced by TOR loss causes growth defects (Layalle et al., between organs is required. If this delicate balance fails, tissue 2008). In consideration of the aforementioned notion that the growth defects may develop. intestine signals to the prothoracic gland, contributing to larval development, we speculate that the prothoracic gland might Stem Cell Actions be a pivotal organ that participates in the regulation of larval What is the regulatory machinery underlying the interorgan development. Additionally, Colombani et al. found that brain- communication that largely controls stem cell actions in larvae? expressed DLGR3 affects growth by regulating the Dilp8-induced While still a work in progress, our understanding in this field developmental delay (Colombani et al., 2015). Colombani et al. has increased significantly in recent years. In fact, apart from has also underscored the important relationships between disc- a few analyses, most conclusions related to the interorgan expressed Dilp8 and developmental timing (Colombani et al., communication responsible for stem cell actions have been 2012). The Dilp8 thus serves as a crucial node in an organ- formulated based on studies conducted in the larval CNS. For organ communication signaling network that governs larval example, the fat body-brain axis, in addition to its role in development. regulating tissue growth, acts as a dedicated channel to affect stem cell capability in the hematopoietic system. Shim et al. Other Biological Processes highlighted the role of IPC-expressed Dilp2 in orchestrating The dialog between hemocytes and somatic muscle has been hematopoietic progenitor fate, suggestive of the causal link identified as playing an important role in the immune response. between the brain and lymph gland (Shim et al., 2012). The fat For example, Upd2 and Upd3 from circulating hemocytes body, which responds to amino acids, stimulates the secretion of activate the JAK/STAT signaling in somatic muscles, which is Dilp2 from IPCs, which is directly sensed by the InR-dTOR-wg implicated in the immune defense against wasp infection (Yang signaling pathway in the medullary zone (Shim et al., 2012). This et al., 2015). Recently, the focus has shifted to the interorgan finding has undoubtedly been instrumental in improving our communication deeply involved in the functional responses of understanding of how signals from the peripheral organs regulate powered organs, particularly the heart. The establishment of hemopoiesis in larvae. Additionally, there are several indications the fat body-heart axis has been confirmed by the interesting that the proliferative capability of neuroblasts (NBs) is also the observation that TOR suppression specifically in the fat body

Frontiers in Cell and Developmental Biology | www.frontiersin.org 12 April 2017 | Volume 5 | Article 29 Liu and Jin The Interorgan Communication in Drosophila causes the dysregulation of heart structure and function (Birse understanding the functions of brain-produced Dilps in stem et al., 2010). However, it remains to be determined how the cell biology will undoubtedly lead to a better understanding of heart receives the signals that mediate its biological function. the functional roles of the brain-gut communication model in Furthermore, it will be interesting to investigate the influences promoting regenerative inflammation and, potentially, cancer. of signals from other organs on heart behavior in the coming Interestingly, brain-expressed Dilp1, but not Dilp2, was identified years. Additionally, a study by Owusu-Ansah et al. identified as facilitating ovarian maturation in the first days of adult life that muscle mitohormesis exerts critical functions in promoting (Liu et al., 2016). It remains largely unknown why different brain- longevity (Owusu-Ansah et al., 2013). A striking finding of produced Dilps control stem cell actions in different biological this study is that the muscle mitohormesis-mediated lifespan systems. To date, few studies have provided essential clues to extension is regulated by mitochondrial unfolded protein answer this question. response (UPRmt) and by Imp-L2 secretion from muscles, Although much progress has been made in our understanding which suppresses insulin signaling in the fat body (Owusu- of intestinal inflammation after acute infection, the detailed Ansah et al., 2013). We have summarized all the information functions of organ-organ communication in regenerative relevant to non-gastrointestinal organ communication axes in inflammation during aging represent an additional mystery. A larvae (presented in Figure 3 and Table 3). In summary, as is pioneering study conducted by Chen et al. elucidated the impacts evident from the scarcity of molecular data, data on organ-organ of organ-organ communication on aging, intensively suggesting communication in larvae remain lacking, with the exception of that the age-related decline in the regenerative capacity of ISCs the brain-fat body communication model, which has witnessed can be affected by age-associated lamin-B loss, specifically in significant development over the last few years. Furthermore, fat body cells during immunosenescence (Chen et al., 2014). In although our understanding of Drosophila gut development is this regard, we speculate that immunosenescence-promoting quite advanced, how this biological process is regulated by factors may go beyond the reduction of lamin-B; other abnormal organ-organ communication in larvae remains largely unknown. signal levels from the fat body might also be responsible for Thus, it will be of significant interest to research the larval age-associated intestinal diseases, a notion that requires further neighbor-gut communication strategies responsible for these gut investigation. In addition to the fat body, signals from other developmental processes in the coming years. organs, such as the brain and body muscle, could accelerate intestinal immunosenescence during aging. However, given that studies on age-related changes in other organs have thus far CONCLUSION AND PERSPECTIVES lagged behind research into the programs underlying intestinal aging, solving this problem is currently difficult. Because aging Studies in the accessible Drosophila model have made is a stressful condition that causes rapid functional defects in significant progress in elucidating the functions of organ- several determinants of the instigation of ISC proliferation, organ communication strategies and the consequences of their accompanied by the emergence of inflammation or cancer- deregulation for homeostatic equilibrium. However, the key related phenotypes, it is also of interest to understand how the issue regarding how the signaling pathways necessary for this aging intestine signals to the peripheral organs, contributing to interorgan communication integrate with each other remains systemic immunosenescence. Several other questions remain for incompletely understood. This review merely outlines some future studies. For example, much progress has been made in of the basic research areas regarding the interactions between our understanding of the role of adult hemocytes in intestinal Drosophila organs and tissues that contribute to the organism’s regeneration. Because most adult hemocytes reside near the homeostasis and health. Several fascinating topics in this field middle midgut (Ayyaz et al., 2015), one of the most important have yet to be clarified and discussed. questions in this field is whether hemocyte-expressed signals also Regenerative inflammatory signals are considered strongly play a multitude of physiological roles in the adult Drosophila associated with organismal health and diseases (Panayidou “stomach.” Additionally, given that the Drosophila MTs possess and Apidianakis, 2013). Notably, there is growing recognition specific receptors that recognize several hormones produced by of the multiple signaling pathways responsible for intestinal the intestinal endocrine system (Johnson et al., 2005; Söderberg regeneration in the adult Drosophila intestine, which are not et al., 2011; Reiff et al., 2015), such as Pdf-R, TK-R, DH31-R, exclusively confined to the intestine itself but also present in the and DH44-R, a more thorough characterization of functional peripheral organs. For example, as discussed earlier, existing data differences among these receptors will provide a necessary link indicate that a stress-induced change in ISC proliferative activity to clarify how the MTs receive different signals from the intestine is caused by Dilp2 from the brain (Amcheslavsky et al., 2009). to regulate the basic biological processes of the renal system. Fundamental questions that have arisen from this preliminary Finally, the similarities between mammals (such as humans) work include the following: Are there other types of Dilps and Drosophila are not limited to their organic elements but that could also contribute significantly to ISC activity? If so, are also evident in their interorgan communication signals what are the exact programs underlying excreted Dilp-induced (Droujinine and Perrimon, 2016). First, several organs in ISC self-renewal? What are the functional differences between Drosophila have human equivalents, including the posterior these Dilps regarding intestinal inflammation? Furthermore, midgut (human small intestine), fat body (human adipose tissue) another challenge will be to determine how all these Dilps and MTs (human kidney) (Droujinine and Perrimon, 2016). might be integrated during this regenerative process. Therefore, Second, it is remarkable that most of the signals identified

Frontiers in Cell and Developmental Biology | www.frontiersin.org 13 April 2017 | Volume 5 | Article 29 Liu and Jin The Interorgan Communication in Drosophila to date in Drosophila organ-organ communication axes have communication continues to be a rich and diverse field, and it counterparts that also regulate communication between organs is likely that data obtained from thorough studies investigating in humans, including myoglianin (human growth differentiation organ-to-organ communication in Drosophila will facilitate the factor (GDF)-11) and Upd2 (human leptin) (Droujinine discovery of similar mechanisms in humans. and Perrimon, 2016). Furthermore, the lessons learned from Drosophila on interorgan communication have striking parallels AUTHOR CONTRIBUTIONS with the situation in humans. For example, as discussed earlier, feeding causes Upd2 production in the fat body, stimulating QL contributed to the writing of this review article. LJ approved the JAK-STAT signaling pathway in GABAergic neurons (Rajan the final version of the manuscript. QL and LJ are accountable for and Perrimon, 2012). Similarly, nutrient-mediated adipokine the entire contents. leptin production in adipose tissue acts on a neuroendocrine organ (brain) via the leptin receptor in humans (Droujinine FUNDING and Perrimon, 2016). However, one difference between the two species is that humans possess bones, blood vessels and The project was supported by the grant from the National Natural adaptive immunity, which do not exist in Drosophila (Droujinine Science Foundation of China (31270923) and the Fundamental and Perrimon, 2016). In conclusion, research into organ-organ Research Funds for the Central Universities (2572016EAJ4).

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Frontiers in Cell and Developmental Biology | www.frontiersin.org 16 April 2017 | Volume 5 | Article 29